1. Field of the Invention
The present invention is directed to a method of reducing the incidence or delaying the onset of diabetes in diabetes-susceptible mammals by the administration to the mammal of an effective amount of a gonadotropin-releasing hormone (GnRH) antagonist. Significantly, GnRH antagonist administration is predicted to prolong the honeymoon phase of diabetes in mammals after a diagnosis of diabetes has been made. Statistically significant reductions in diabetes incidence and/or onset as well as a prolongation of the honeymoon phase of diabetes are predicted to occur after administration of such antagonists.
2. Description of the Prior Art
There are 15.7 million people (5.9% of the population) in the United States who have diabetes. An estimated 10.3 million people have been diagnosed with diabetes, while 5.4 million people are unaware that they have a disease. Each day approximately 2,200 people are diagnosed with diabetes. Diabetes is the seventh leading cause of death (sixth-leading cause of death by disease) in the United States. Diabetes is a chronic disease that has no cure. Diabetes is one of the most costly health problems in America. Health care and other costs directly related to diabetes treatment, as well as the costs of lost productivity, are believed to be $98 billion annually.
Diabetes is a disease in which the body does not produce or properly use insulin, a hormone that is needed to convert sugar, starches and other food into energy needed for daily life. The exact causes of diabetes remain a mystery, although both genetics and environmental factors such as obesity and lack of exercise appear to play roles. There are two major types of diabetes:                Type 1. An autoimmune disease in which the body does not produce any insulin, most often occurring in children and young adults. People with Type 1 diabetes must take daily insulin injections to stay alive. Type 1 diabetes accounts for 5-10 percent of diabetes.        Type 2. A metabolic disorder resulting from the body's inability to make enough, or properly use insulin. It is the most common form of the disease. Type 2 diabetes accounts for 90-95 percent of diabetes. Type 2 diabetes is nearing epidemic proportions, due to an increased number of older Americans, and a greater prevalence of obesity and sedentary lifestyles.        
Type 1 diabetes results from an autoimmune process in which the body's immune system attacks and destroys the insulin producing cells of the pancreas. Because glucose cannot enter the cells, it builds up in the blood and the body's cells literally starve to death. People with Type 1 diabetes must take daily insulin injections to stay alive.
The strikingly increased incidence of certain autoimmune diseases in females compared to males is well accepted. Although there is evidence that androgens and estrogens play a role in the pathogenesis of autoimmunity, the exact roles of gonadal steroids in autoimmune diseases remain unclear. A number of studies in experimental models have shown that gonadectomy modifies the expression of autoimmune diseases, including diabetes. (Roubinian, et al., (1978) Effect of Castration and Sex Hormone Treatment on Survival, Anti-nucleic Acid Antibodies, and Glomerulonephritis in NZB/NZW F1 Mice. J. Exp Med, 147, 1568-83; Hawkins, et al., (1993) The Effect of Neonatal Sex Hormones on the Incidence of Diabetes in Nonobese Diabetic Mice. Proc. Soc. Exper. Biol. Med, 202, 201-205; Makino, et al., (1981) The Effect of Castration on the Appearance of Diabetes in Nod Mouse. Exp Anim, 30; and Fitzpatrick, et al., (1991) Influence of Castration, along or Combined with Thymectomy, on the Development of Diabetes in the Non-obese Diabetic Mouse. Endocrinology, 129, 1382-1390)
However, most studies of gender differences in autoimmunity are performed in vivo, where manipulations such as gonadectomy or administration of gonadal steroids will necessarily alter feedback effects on hypothalamic and pituitary hormones, some of which are now known to be immunomodulatory. One hypothalamic hormone with immunomodulatory properties is gonadotropin-releasing hormone (GnRH) (also known as luteinizing hormone releasing hormone (LHRH)). GnRH is known to possess indirect immunomodulatory properties via its regulation of gonadal steroids. GnRH has been shown to exert direct immunomodulatory effects in vitro and in vivo in gonadectomized rats. GnRH agonists can prevent the involution of the thymus gland which normally occurs with aging in the rat (Marchetti, et al., (1989) Luteinizing Hormone-releasing Hormone (LHRH) Agonist Restoration of Age-associated Decline of Thymus Weight, Thymic LHRH Receptors, and Thymocyte Proliferative Capacity. Endocrinology, 125, 1037-45). GnRH agonist administration has been associated with increases in B and T cell proliferative responses and in an increase in the number of T lymphocytes expressing the I1-2 receptor in rats (Morale, et al., (1991) Blockade of Central and Peripheral Luteinizing Hormone-releasing Hormone (LHRH) Receptors in Neonatal Rats with a Potent LHRH-antagonist Inhibits the Morphofunctional Development of the Thymus and Maturation of the Cell-mediated and Humoral Immune Responses. Endocrinology, 128, 1073-85; and Batticane, et al., (1991) Luteinizing Hormone-releasing Hormone Signaling at the Lymphocyte Involves Stimulation of Interleukin-2 Receptor Expression. Endocrinology, 129,277-86). Moreover, spleen and thymus preparations have been shown to contain mRNA for GnRH and to produce an immunoreactive GnRH (Emanuele, et al. (1990) Rat Spleen Lymphocytes Contain an Immunoactive and Bioactive Luteinizing Hormone-releasing Hormone. Endocrinology, 126,2482-6; and Maier, et al., (1992) Thymocytes Express a mRNA That is Identical to Hypothalamic Luteinizing Hormone-releasing Hormone mRNA. Cell Mol Neurobiol, 12, 447-54). A recent study demonstrates that lymphocytic GnRH production increases when T-cells are activated by PHA in vitro (Azad, et al., (1993) Immunoactivation Enhances the Concentration of Luteinizing Hormone-releasing Hormone Peptide and its Gene Expression in Human Peripheral T-lymphocytes. Endocrinology, 133, 215-23). Thus, GnRH appears to exert generally stimulatory effects on the immune system.